Highly Immunoreactive IgG Antibodies Directed against a Set of Twenty Human Proteins in the Sera of Patients with Amyotrophic Lateral Sclerosis Identified by Protein Array

May, Caroline; Nordhoff, Eckhard; Casjens, Swaantje; Turewicz, Michael; Eisenacher, Martin; Gold, Ralf; Brüning, Thomas; Pesch, Beate; Stephan, Christian; Woitalla, Dirk; Penke, Botond; Janáky, Tamás; Virók, Dezső; Szabó, László; Engelhardt, J.; Meyer, Helmut E.

doi:10.1371/journal.pone.0089596

Cited by 36 publications

(28 citation statements)

References 58 publications

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“…Seminal studies in the 1980s showed that ALS patients have a high frequency of monoclonal paraproteinemia (115) and a high incidence of autoimmune disorders (116). Numerous IgG antibodies and complement proteins are found in sera (117) from ALS patients, and antibody titer was positively associated with increased disease severity (118). Monoclonal Igs were detectable in 60% of sporadic ALS patients (119), and autoantibodies against ganglioside GM1 and GD1a (120), sulfoglucuronylparagloboside (121), neurofilament proteins (121), the TNF receptor family member FAS (CD95) (122), and voltage-gated Ca 2+ channels (123,124) have all been reported, indicating that ALS patients generate antibody responses to a variety of autoantigens.…”

Section: Inflammation and Autoimmunity In Als/ftdmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

145

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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Section: Inflammation and Autoimmunity In Als/ftdmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

145

102

View full text Add to dashboard Cite

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“…Additionally, a study published by May et al (2014), using the same microarray platform as well as a similar biomarker discovery strategy identified 20 differentially expressed autoantibodies with the potential to distinguish amyotrophic lateral sclerosis (ALS) samples from healthy controls. Twenty ALS serum samples were differentiated from 20 control samples with a sensitivity of 99.9%, and a specificity of 100.0%, thus validating the use of Invitrogen's human protein microarray as a biomarker discovery platform as well as confirming the utility of Random Forest in biomarker verification (May et al, 2014).…”

Section: Disease-specific Autoantibody Profiles Using Human Protein Mmentioning

confidence: 99%

Utility of Autoantibodies as Biomarkers for Diagnosis and Staging of Neurodegenerative Diseases

DeMarshall

Sarkar

Nägele

et al. 2015

International Review of Neurobiology

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“…While these two studies were based on investigations of reactivity to proteins already suggested to be involved in disease pathology, May and colleagues instead used a more unbiased approach. They analyzed serum IgG reactivity toward more than 9000 full-length proteins in 20 ALS and 20 nondiseased controls and identified 20 proteins displaying increased ALS reactivity, several with CNS-related functions [115].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Neuroproteomic profiling of human body fluids

Häggmark

Schwenk

Nilsson

2015

Proteomics Clinical Apps

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"The seat of the soul and the control of voluntary movement -in fact, of nervous functions in general, -are to be sought in the heart. The brain is an organ of minor importance, perhaps necessary to cool the blood."Aristotle (De motu animalium) AbstractThis thesis provides results from affinity based studies where human body fluids were profiled to find markers for neurological diseases. Both proteins and autoantibodies were analysed using microarray technologies that can profile hundreds of analytes and hundreds of samples in parallel using small sample volumes. A central element in this work was to develop and apply new methods to study cerebrospinal fluid (CSF), which is the fluid in direct contact with the brain. CSF contains proteins reflecting the physiological state of the central nervous system and therefore offers a unique insight into proteins associated to neurological disorders. As a complement to CSF, bloodderived samples such as serum and plasma, were also investigated as these represent potential sources of disease related proteins. The work presented here summarises the development of assay protocols to study protein and autoantibodies in CSF and blood using planar and bead-based microarrays.In Paper I, an antibody-based protocol was developed to enable multiplexed protein profiling in CSF. The protocol was then applied for a first analysis within multiple sclerosis (MS) patients. In Paper II, the results were further evaluated in additional CSF as well as plasma samples. Based on the CSF analysis we found two proteins associated to MS; GAP43, a protein related to disease progression and SERPINA3, a protein involved in inflammation. In addition, four other proteins; IRF8, METTL14, IL7 and SLC30A7, were found to have altered plasma levels between the patient groups. The expression of these proteins were further investigated by immunofluorescent staining of human brain tissue, revealing differential localisation of proteins in diseased and healthy brain. In Paper III, a study on extensive protein profiling of plasma in the context of another neurodegenerative disorder, amyotrophic lateral sclerosis (ALS), is described. The levels of three proteins, namely NEFM, RGS18 and SCL25A20, were found to be elevated in ALS patients compared to controls. Among these, NEFM also indicated association to disease subtype as the levels were elevated in patients with definite compared to suspected diagnosis.In addition to antibodies, we also utilised antigens on microarrays to screen for the presence of autoantibodies in body fluids. In Paper IV, a strategy for this analysis was developed using protein fragments and two types of microarrays. This strategy was then applied for profiling of the autoantibody repertoire of MS patients, revealing 51 protein fragments with potential disease relevance. Interestingly, comparison of plasma and CSF samples obtained from the same patients indicated high concordance of antibodies between the two body fluids. In Paper V, a similar strategy was applied to narcolepsy, another neu...

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Highly Immunoreactive IgG Antibodies Directed against a Set of Twenty Human Proteins in the Sera of Patients with Amyotrophic Lateral Sclerosis Identified by Protein Array

Cited by 36 publications

References 58 publications

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Utility of Autoantibodies as Biomarkers for Diagnosis and Staging of Neurodegenerative Diseases

Neuroproteomic profiling of human body fluids

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